Published OnlineFirst September 15, 2009; DOI:10.1158/1055-9965.

EPI-08-1167

Sexually Transmitted Infections and Prostate Cancer among

Men in the U.S. Military
Leslie K. Dennis, Julie A. Coughlin, Brittany C. McKinnon, et al.
Cancer Epidemiol Biomarkers Prev 2009;18:2665-2671. Published OnlineFirst September 15, 2009.

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2665

Sexually Transmitted Infections and Prostate Cancer

among Men in the U.S. Military
Leslie K. Dennis,1 Julie A. Coughlin,1 Brittany C. McKinnon,1 Timothy S. Wells,2
Charlotte A. Gaydos,3 Eva Hamsikova,4 and Gregory C. Gray1
1
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; 2Air Force Research Laboratory,
Wright-Patterson Air Force Base, Dayton, Ohio; 3Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland; and
4
Department of Experimental Virology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

Abstract
Studies of self-reported sexually transmitted infections
(STI) suggesting an association with prostate cancer may
reflect underreporting of such infections among nondiseased subjects. To reduce such bias, we studied archived
sera in a cohort of U.S. military personnel known to have
high rates of both STIs and prostate cancer. Using a
nested case-control design, serum samples from 534 men
who served on active duty between September 1, 1993
and September 1, 2003 were examined. Controls were individually matched to cases based on date of serum collection, date of birth, branch of service, military rank,
marital status, and race. Each of the 267 case-control pairs
had two serum samples: a recent serum sample, taken
1 year before the case's prostate cancer diagnosis, and
an earlier serum sample, taken 8 years before diagnosis.
Each serum specimen was studied for antibodies against

human papillomavirus, herpes simplex virus-2 (HSV-2),

and Chlamydia trachomatis. Logistic regression accounted for matching and potential confounding factors.
Study data indicated no association between prostate
cancer and serologic evidence of infections just before
the reference date. However, a statistically significant association between prostate cancer and serologic evidence
of HSV-2 infection was detected in the earlier sample
(odds ratio, 1.60; 95% confidence interval, 1.05-2.44).
The strength of this association increased when analyses
were restricted to sera collected at least 60 months before
diagnosis (odds ratio, 2.04; 95% confidence interval, 1.263.29; 204 pairs). If this association is causal, then our findings would suggest a long latency period for prostate
cancer development after HSV-2 infection. (Cancer Epidemiol Biomarkers Prev 2009;18(10):266571)

Introduction
One in six men is likely to be diagnosed with prostate
cancer in his lifetime. In 2009, an estimated 192,280 cases
of prostate cancer will be diagnosed in the United States
and 27,360 men will have died of prostate cancer (1). Although prostate cancer is a leading cause of cancer morbidity and mortality in men, few risk factors for prostate
cancer have been established.
Infectious agents have been associated with a diverse
group of cancers including liver, cervix, stomach, nasopharynx, bladder, bile duct, and Kaposi sarcoma (2). Inflammation may both induce and promote cancer
through exposure to highly reactive compounds and
growth factors and increased cell turnover (3). A review
of studies of prostatitis and prostate cancer showed evidence of an increased risk of prostate cancer among
men with prior prostatitis (4). It is unclear if inflammation
affects the risk of prostate cancer or if it influences a surveillance bias. A meta-analysis evaluating aspects of sexual activity and prostate cancer suggested an association
between prostate cancer and sexually transmitted infections [STI; relative risk, 1.4; 95% confidence interval

Received 12/5/08; revised 7/13/09; accepted 7/29/09; published OnlineFirst 9/15/09.

Grant support: Department of Defense, Prostate Cancer Research Program of the
Congressionally Directed Medical Research Programs grant W81XWH-04-1-0163.
Requests for reprints: Leslie K. Dennis, Department of Epidemiology, College of
Public Health, University of Iowa, 200 Hawkins Drive C21-G GH, Iowa City, IA 52242.
E-mail: leslie-dennis@uiowa.edu
Copyright 2009 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-08-1167

(95% CI), 1.2-1.7; ref. 5]. However, this was based

on self-report rather than on biomarkers. A 2005 metaanalysis on prostate cancer and STIs, which included
studies measuring human papillomavirus (HPV) by
either serology or PCR, suggested an increased risk of
prostate cancer with HPV infection [odds ratio (OR), 1.5;
95% CI, 1.1-2.1; ref. 6].
According to the National Health and Nutrition Examination Survey III of individuals ages 12 years, herpes
simplex virus-2 (HSV-2) was prevalent in 21.9% of individuals in the United States in 1988 to 1994 (7). The prevalence of STIs among U.S. military personnel has been
estimated to be higher than that among civilians (8). A
1989 to 1991 study of deployed U.S. military personnel
found that they frequently engaged in high-risk sexual behavior and had high rates of STIs (9). Military personnel
had a high prevalence of STIs caused by Chlamydia trachomatis, HSV-2 infection, and HPV (8). Based on a study in
North Carolina in 1996, rates of C. trachomatis among individuals in the military were 4-fold higher than rates
among similar nonmilitary individuals in North Carolina
and the United States (10).
The U.S. military health-care system affords an opportunity to study prostate cancer risk in a relatively homogeneous and young population compared with the
general U.S. population. Prostate-specific antigen (PSA)
screening is a covered health benefit in the military; thus,
men in the military are more likely to have had PSA
screening ordered in accordance with published guidelines than are men in the general population. As a result,

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undiagnosed prostate cancer is less likely to occur in men

who are members of the U.S. military compared with similar civilian groups. Prior studies among military populations have reported both high rates of prostate cancer (11)
and high rates of STIs (8-10, 12); thus, if an association exists between STIs and prostate cancer, it is likely to be observed in this population.
Previous meta-analyses evaluating prostate cancer
suggest an association between prostate cancer and STIs
(5, 6); however, most of the pooled data were based on
self-report, and as STIs often reflect undesirable behavior,
they are subject to considerable reporting biases. The
goal of this study was to eliminate recall bias by examining STIs and prostate cancer associations through analysis of sera collected in a cohort of military personnel
before prostate cancer diagnosis. An increased relative
risk for prostate cancer after STIs would suggest a possible infectious component in the development of prostate
cancer, which could have several important public health
implications.

Materials and Methods

We conducted a matched case-control study nested within the U.S. military population. Regular active-duty personnel are periodically evaluated by serologic test for HIV
infection and an aliquot of their sera is preserved in the
Department of Defense Serum Repository. The Serum Repository also stores pre- and post-deployment sera for all
active-duty, Guard, and Reserve U.S. service members.
Subjects testing positive for HIV were not eligible for
study. The eligible subjects for this study were active-duty
men, ages 18 years, serving in the U.S. Army, Air Force,
Navy, or Marine Corps during the study period from September 1, 1993 to September 1, 2003, with at least 2 years
of active-duty service before their reference date. The reference date for the matched pair was the diagnosis date of
prostate cancer. For each case, the Department of Defense
Serum Repository collected an aliquot from each of two
serum samples, with the recent serum sample most closely preceding the prostate cancer diagnosis and the earlier
serum sample most distant from the cancer diagnosis.
Both of the control's serum samples were matched to
the case's serum draw dates within 90 days. To allow
for two serum samples, we required both cases and controls to have served at least 2 years of active-duty service
before their reference date.
Cases. Prostate cancer cases were identified using International Classification of Diseases, Ninth Revision, Clinical
Modification diagnostic code 185 in electronically maintained Department of Defense hospitalization records.
To identify prostate cancer cases, hospitalization data
were obtained from the Standard Inpatient Data Record
and the Health Care Service Record. Standard Inpatient
Data Record and Health Care Service Record are computerized databases of standardized discharge diagnoses for
hospitalizations within the Military Health System and
for hospitalizations billed to the Department of Defense
by private facilities. Cases were validated using either
procedure codes, pathology reports, or the Department
of Defense Automated Central Tumor Registry. Information from the patient's first encounter with prostate cancer
in either Standard Inpatient Data Record or Health Care
Service Record was merged with demographic and mili-

tary data at the time of entry into the study and at the
time of diagnosis. Men who were diagnosed with prostate
cancer before September 1, 1993 or had a prostate cancer
diagnosis that could not be validated were excluded.
Controls. Controls were selected by random number
procedure in an equal number as cases (1:1 matched to
cases) from the remaining military personnel who had
not been diagnosed with prostate cancer. Controls were
matched to cases based on specific factors (as follows)
at the time of diagnosis of the case. Matched controls were
active-duty at the time the case was diagnosed and had a
serum specimen collected within 90 days of the case (for
each of two specimens). Our matching criteria included
date of birth (1 year), branch of service (Army, Air Force,
Marines, and Navy), and military rank (enlisted and officer). Based on standard matching criteria, the Department
of Defense Serum Repository staff also matched controls
for marital status (married, never married, or other) and
race (White, Black, or other), which we were informed of
after receiving the sera.
Of the 398 eligible cases identified, 89 did not have adequate sera or sera volume necessary to conduct the STI
analyses. Of the remaining 309 cases, 41 could not be
matched to an appropriate control, leaving 268 cases
matched to 268 controls. One subject only had a recent
serum; thus, this matched pair was excluded, leaving
267 matched pairs. Institutional review board approval
was sought and granted.
Exposure Assessment. Sera aliquots from the Department of Defense Serum Repository were shipped on dry
ice to researchers at the University of Iowa and were
stored at 80C. Serum specimens were then split and
sent to separate laboratories for STI serologic testing.
The laboratories that performed the serologic assays were
blinded with respect to case-control status.
HSV-2 antibody tests were done using the HerpeSelect
2 ELISA IgG Test kit (Focus Technologies). The manufacturer's instructions stated that an index value <0.90 was
considered negative, >0.90 to <1.10 was considered equivocal, and >1.10 was considered positive. Analyses were
interpreted by including equivocals with negatives so that
<1.10 was considered negative and >1.10 as positive. HPV
analyses were done using an ELISA assay for IgG antibodies to virus-like particles derived from HPV6, HPV11,
HPV16, and HPV18 (13). Each microtiter plate included
a positive control and a negative control. Analyses of sera
were run in duplicate and averaged. Positive results were
defined as an absorbance index >1.0. All samples that
showed large differences in absorbance between parallel
wells, those with absorbance in the range of 20% above
the cutoff value, and 15% to 20% of randomly selected
samples in the set were retested to confirm results. Tests
for antibodies to C. trachomatis were done using the
microimmunofluorescence method described by Wang
et al. (14) for serotypes B to K. This method detects antibodies to pooled serogroups BED (B-group), CJHI (Cgroup), and GFK (intermediate group) of C. trachomatis.
Any result >1:16 was considered positive for antibodies
to C. trachomatis.
Analyses. Descriptive statistics were used to compare
cases and controls for time between sera collection and
matching variables. Logistic regression conditioned on
the one-to-one matching of controls to cases was used to

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Cancer Epidemiology, Biomarkers & Prevention

Table 1. Demographic characteristics of active-duty U.S.

military men at time of entry into study, 1993 to 2003,
compared with matched case-control pairs
Matched
case-control pairs
(n = 267), n (%)
Age (y)
<36
36-40
41-45
46-50
>50
Military rank
Enlisted
Officer
Service branch
Army
Air Force
Marines
Navy
Marital status
Married
Not married
Race
White non-Hispanic
Black non-Hispanic
Other

4
14
82
80
87

(1.5)
(5.2)
(30.7)
(30.0)
(32.6)

116 (43.4)
151 (56.6)
117
35
20
95

(43.8)
(13.1)
(7.5)
(35.6)

analyses by marital status (married versus all others) and

race (Blacks versus all others). Analyses were also conducted on specific subtypes of HPV and C. trachomatis as
described under the exposure assessment section above.
To further examine the potential latency period, for the
earlier serum (collected an average of 7.8 years before diagnosis), we ran a second model excluding any pairs that
had their sera collected <60 months before diagnosis. A
dose-response variable for the number of STIs a subject
had (0, 1, or 2-3) was computed across HSV-2, HPV16
or HPV18, and C. trachomatis. Due to the small number
of subjects with 3 STIs (8 on early serum and 12 on recent
serum), subjects with either 2 or 3 STIs were pooled together. Analyses treated the number of STIs as a categorical variable, and then we reran the analyses with the
three categories of STIs (0, 1, or 2-3) as a continuous variable to compute the Ptrend and a trend OR. We report the
difference in this trend comparing the lowest category (no
STIs) to the highest category (2-3 STIs). The trend OR fits a
line to the coefficients for each category, assuming an
equal increase in the log (OR) for each category level
(15). Ptrend values are reported for ordered categorical
variables.

Total military*
(n = 2,761,151),
n (%)
2,464,703
183,820
81,311
25,784
5,533

(89.3)
(6.7)
(2.9)
(0.9)
(0.2)

2,469,243 (89.4)
291,908 (10.6)
961,756
576,547
412,873
754,986

(35.5)
(21.3)
(15.3)
(27.9)

237 (88.8)
30 (11.2)

1,055,375 (38.2)
1,705,776 (61.8)

192 (71.9)
67 (25.1)
8 (3.0)

1,931,664 (70.0)
474,932 (17.2)
354,555 (12.8)

*Active duty for at least 6 months during September 1, 1993 to September 1,

2003.

Age at reference date (the case diagnosis date).

Results
The distribution of demographic factors in our casecontrol study compared with the total military population
over the study period is described in Table 1. Because
controls were matched to cases on several of these variables, we list the number of matched pairs for characteristics in Table 1. The minimum length of service among
our 267 matched pairs was 3.5 years, with an average
length of service of 22.4 years among cases and 21.1 years
among controls. Subjects differed from all active-duty
military with respect to age, military rank, marital status,

examine associations between STIs and prostate cancer.

Analyses examined potential confounding due to length
of service beyond confounding controlled for by one-toone matching on date of birth (and other matching factors). Although matching factors could not be examined
in the analyses, we stratified the data by date of birth to
examine STI analyses separately for older and younger
subjects (<50 and 50 years). Similarly, we ran stratified

Table 2. Crude ORs for 267 matched pairs of prostate cancer cases and controls for elevated antibodies against
HSV-2, HPV, and C. trachomatis

Recent serum: mean 10 mo before diagnosis

HSV-2
HPV16 or HPV18
Any HPV (6, 11, 16, or 18)
C. trachomatis

Earlier serum: mean 94 mo before diagnosis

HSV-2
HPV16 or HPV18
Any HPV (6, 11, 16, or 18)
C. trachomatis

Cases
139
55
182
37
128
63
207
29

Cases

156
56
179
43
122
61
205
31

Controls, n (%)

OR (95% CI)

OR (95% CI)

All subjects

Restricted subjects*

(52.1)
(20.6)
(68.2)
(13.9)
(47.9)
(23.6)
(77.5)
(10.9)

+
47
26
40
8
59
17
27
4

(17.6)
(9.7)
(15.0)
(3.0)
(22.1)
(6.4)
(10.1)
(1.5)

Reference
1.17 (0.79-1.73)
Reference
0.92 (0.59-1.45)
Reference
1.07 (0.75-1.52)
Reference
1.07 (0.64-1.81)

Controls, n (%)

OR (95% CI)

OR (95% CI)

All subjects

Restricted subjects*

Reference
1.60 (1.05-2.44)
Reference
1.13 (0.73-1.75)
Reference
0.98 (0.69-1.40)
Reference
1.35 (0.79-2.31)

Reference
2.04 (1.26-3.29)
Reference
1.20 (0.74-1.95)
Reference
1.00 (0.67-1.50)
Reference
1.80 (0.96-3.38)

(58.4)
(21.0)
(67.0)
(16.1)
(45.7)
(22.8)
(76.8)
(11.6)

+
35
20
38
7
62
22
23
8

(13.1)
(7.5)
(14.2)
(2.6)
(23.2)
(8.2)
(8.6)
(3.0)

NOTE: HSV-2 index value is positive for >1.1, HPV optical density value is positive for >1; and C. trachomatis titer value is positive for >1:16.
Matched on the following characteristics at the reference date: date of birth, branch of service, military rank, date of serum specimen, marital status, and race.
*Subjects whose earlier serum was collected >60 mo (60-166 mo) before diagnosis (n = 204 pairs).

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Table 3. Dose-response ORs among 267 matched pairs of prostate cancer cases and controls for an increasing of
number of STIs (HPV16 or HPV18, HSV-2, or C. trachomatis)
No. STIs*

Recent serum
No. cases
0
1
2-3

No. controls

OR (95% CI)
Restricted subjects

2-3

All subjects

97
45
19

31
26
9

19
16
5

1.0 (reference)
1.50 (0.99-2.28)
0.94 (0.56-1.58)
Ptrend = 0.660
1.12 (0.68-1.83)

Linear trend for increase of 2 STIs

Earlier serum
No. cases
0
1
2-3

OR (95% CI)

102
47
20

29
27
11
Linear trend for increase of 2 STIs

16
7
8

1.0 (reference)
1.47 (0.96-2.24)
1.54 (0.88-2.69)

1.0 (reference)
1.83 (1.10-3.04)
1.86 (1.00-3.44)

Ptrend = 0.054
1.67 (0.99-2.81)

Ptrend = 0.012
2.10 (1.18-3.77)

NOTE: Matched on the following characteristics at the reference date: date of birth, branch of service, military rank, date of serum specimen, marital status,
and race.
*Number of positive STI antibody analyses: 1 = at least one positive result, 2 = at least two positive results, and 3 = all three positive. STIs that were counted
for a positive: HSV-2, HPV (16 or 18), or any antibodies for C. trachomatis.

Subjects whose earlier serum was collected >60 mo before diagnosis (n = 204 pairs).

and race (Table 1). Given that pairs were matched based
on these factors, Table 1 data suggest that older men,
officers, married men, and Blacks were more likely to be
diagnosed with prostate cancer than their military peers.
However, the higher proportion of officers in our nested
case-control study could be related to older age or higher
socioeconomic status or may be due to more years of service (23.2 years for officers and 19.9 years for enlisted; P <
0.0001 for t test of the difference).
The recent serum was drawn an average of 10 months
before the reference date (median, 5 months; range, 0-76
months). The average, median, and range of follow-up
time after the earlier serum draw were 94, 93, and 15 to
166 months, respectively.
Among all subjects, 126 men had elevated antibodies
for HSV-2 in both serum samples; for 28 subjects, tests
of the earlier sample were negative, whereas tests of the
more recent sample were positive. Among the 5 subjects
that showed evidence of elevated antibodies for HSV-2 in
the early sample but not in the more recent sample, 2 had
borderline negative values in the more recent sample.
HPV antibodies were elevated in both serum samples
for 124 men; for 32 subjects, tests of the earlier sample
were negative, whereas tests of the more recent sample
were positive. In addition, 42 samples tested positive then
negative. In tests for Chlamydia, 34 men had elevated antibodies in both serum samples, 30 tested negative on the
earlier sample and positive on the recent sample, and 36
were positive then negative on the earlier and recent serum samples, respectively.
No associations were observed between prostate cancer
and elevated STI antibodies measured in recent serum
samples (Table 2). However, an association was seen with
elevated antibodies against HSV-2 in the earlier serum. Because most risk factors for cancer have a latency period of
several years or decades, we further restricted the analyses
of the earlier serum to the subset collected at least 60
months (5 years) before the reference date. When the earli-

er serum antibody analyses were restricted to these 204

case-control pairs, the OR (95% CI) for HSV-2 increased
slightly to 2.04 (1.26-3.29) and an increased association that
was marginally significant was seen between C. trachomatis
infection and the occurrence of prostate cancer (OR, 1.80;
95% CI, 0.96-3.38). When positive results for HSV-2 were
categorized as weak (index value >1.1-3.5) and strong (index value >3.5) for the earlier serum assays, a significant
increasing trend (P = 0.003) was seen for risk of prostate
cancer (data not shown). No associations were found between prostate cancer and elevated antibodies to any
HPV (Table 2). Type-specific analyses of HPV6, HPV11,
HPV16, or HPV18 also showed no associations with prostate cancer (data not shown). A positive but nonsignificant
association was observed between prostate cancer and increased antibodies to C. trachomatis serogroup GFK in the
earlier serum samples (OR, 1.83; 95% CI, 0.68-4.96; data not
shown). Finally, an analysis was conducted to look at the
association between number of STIs (HSV-2, HPV16 or
HPV18, or C. trachomatis) and prostate cancer (Table 3) using a linear dose-response model. No association was seen
with the recent serum (collected just before diagnosis). For
the earlier serum, a linear increase in risk of 110% was seen
for two additional STIs among matched pairs whose specimens were collected at least 60 months before diagnosis
(45% for an increase of one STI). None of these analyses
were confounded by length of service.
Additional analyses of the 267 matched pairs were
stratified by age (<50 and 50 years), marital status,
and race. Analyses showed slightly stronger risks for subjects ages <50 years (OR, 1.92; 95% CI, 1.17-3.14; n = 324),
single men (OR, 1.77; 95% CI, 0.40-7.39; n = 34), and Black
men (OR, 1.74; 95% CI, 0.87-3.47; n = 134) with evidence
of HSV-2 infection in the earlier serum. Although the
mean age of Black men was younger than that of White
men (45 versus 48 years), age did not confound the association between prostate cancer and HSV-2 among Blacks.
Differences were not seen in the recent serum.

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Discussion
STIs have been implicated in several studies as a risk factor for prostate cancer. Although previous meta-analyses
evaluating prostate cancer and STIs showed an increased
risk (5, 6), most of the evidence was based on self-report,
which can be strongly biased. With a goal of reducing
such biases, our study examined associations between
STIs and prostate cancer using sera collected in a cohort
of military men before prostate cancer diagnosis. Intriguingly, our data based on the earlier serum specimens, collected on average 7.8 years before prostate cancer
diagnosis, showed an increased risk of prostate cancer
among men who had elevated antibody titers against
HSV-2. The association with HSV-2 was strengthened
when analyses of the earlier sera were restricted to those
specimens collected at least 5 years before diagnosis. If
HSV-2 infection is causally related to prostate cancer, then
our findings would suggest a long latency period after
HSV infection. This is important in that most risk factors
for cancer show a latency period of many years.
The increased risk for prostate cancer with a longer latency should be further examined in other populations
with high levels of HSV-2 infections using serology with
an adequate length of time between sera collection and
prostate cancer diagnosis. A previous study of HSV-2 serology with an average of 17 years follow-up to prostate
cancer diagnosis found no association; however, that
study differed from our study of U.S. military personnel
in several ways. The Finnish study population had a low
prevalence of elevated antibodies against HSV-2 (16),
which may have limited the study's power to detect an
association among their 163 cases and 288 controls. The
lower prevalence may in part be due to older age of their
cases (age 75 years on average) compared with our average diagnosis age of 48 years. Both of these average ages
are a bit extreme with a median age of diagnosis of 68
years in the United States (1). It is also possible that deterioration of samples over 20 years before analyses may
have affected the data in the Finnish study. Their sera
were collected between 1968 and 1972, and prostate cancer cases were diagnosed through 1991. Thus, cases (and
their matched controls) were apparently linked to sera
sometime between 1991 and when the article was submitted for publication (2004). Other previous studies relied
on self-report as a measure of exposure (17, 18) or collected data on HSV-2 infection post-diagnosis of prostate cancer (19-21). Self-report of STIs is problematic with a high
potential for underreporting especially among nondiseased subjects. Although HSV-2 has been reported to infect prostate tissue (19), diagnosis of STIs after prostate
cancer lacks the appropriate temporal sequence to suggest
causation. In addition to the lack of a temporal sequence,
a mechanism for HSV-2 initiating or promoting prostate
cancer has not been identified. As HSV-2 infections are
seldom completely cleared from the body, antibodies
against HSV-2 may fluctuate over time, especially after
clinical flare-ups. Thus, future research may want to consider examining antibody levels over time.
The lack of association between prostate cancer and evidence for HPV or C. trachomatis infection for our earlier
serum specimens (longer latency) is supported by a few
other studies. A study with at least 10 years follow-up
to prostate cancer found no association with C. trachomatis
infection (22). In addition, no association was seen with

HPV16, HPV18, or HPV33 infection in a nested casecontrol study where the majority of prostate cancer cases
were seen 10 years after infection (23). Another study
with 20 years of follow-up found no association with C.
trachomatis, HPV11, or HPV33 infection but found an increase in risk with HPV18 infection (OR, 2.6; 95% CI, 1.25.8) and a suggested increase with HPV16 infection (OR,
2.4; 95% CI, 0.7-7.6; ref. 24). In a nested case-control study
with case diagnoses occurring an average of 26 years after
enrollment, a marginal association with HPV16 infection
(OR, 2.7; 95% CI, 0.9-7.9) was found (25). Overall, these data suggest no association between prostate cancer and C.
trachomatis infection but a possible association with
HPV16 and HPV18 infections many years after prostate
cancer diagnosis that merits further examination.
We found no association between increased STI antibodies and prostate cancer in the recent serum specimens
(collected an average of 10 months before prostate cancer
diagnosis). This is similar to a recent study by Huang et al.
(26), which found no association between prostate cancer
and elevated antibodies against HSV-2, HPV16, HPV18, or
C. trachomatis in sera collected an average of 18 months before diagnosis. However, in a subset analysis, they did find
an association between prostate cancer and elevated IgA
antibodies against C. trachomatis among Blacks. We did
not see this same association among Blacks in our study.
Another study with a mean time between blood draw
and diagnosis of only 3.1 years also found no association
with HPV16, HPV18, HPV33, or C. trachomatis infection
(27). Two additional studies using sera collected after diagnosis found no association with HPV16 or HPV18 infection
(28, 29). Thus, the seroepidemiologic literature does not support an association between prostate cancer and recent STI.
To study the relationship between prostate cancer and
STIs (without recall bias), it was necessary both to have a
large repository of serum samples collected before diagnosis and to have recent samples and samples collected
over 5 years before diagnosis. The Department of Defense
Serum Repository was the only source, to our knowledge,
that provided such a capability. As a result of using a military population for this study, the median age for prostate cancer cases in this study was 48 years. This is
considerably less than the median age for prostate cancer
cases in the general population, which is 68 years (1). As a
result, the etiology of prostate cancer causation in younger men may not represent that observed among older
men who comprise the majority of prostate cancer cases.
For example, STIs more commonly occur among younger
men rather than among men of advanced age who would
normally be at risk of prostate cancer. Based on what we
know about cervical cancer, 75% of 40 reviewed studies
suggested a latency period of <12 months after HPV infection (30); latency periods between infections and cancer
are believed shorter than for other cancer exposures. Because men ages 18 to 29 years are at greatest risk for STIs,
we would expect such an exposure to cause prostate
cancer at an earlier age if the association is real; thus,
the use of a military population to study STIs and prostate
cancer was deemed appropriate.
The association between STIs and prostate cancer remains controversial. The effects of infections, in general,
on prostate cancer are not clearly understood. Studies of
prostate cancer have examined associations with inflammation and other conditions, such as epididymitis, cirrhosis, urethritis, and several infectious agents, including

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Sexually Transmitted Infections and Prostate Cancer

Trichomonas, cytomegalovirus, and EBV but results have

been inconsistent (31-36). The effects of STIs on prostate
cancer etiology are not clearly understood given the inconsistent findings in studies of other infections. HSV-2 was
found early on in prostate tumors (19, 37); however, more
recent corroborating data seem to be lacking. It is possible
that men with HSV-2 are followed more closely than uninfected men and may be screened for prostate cancer at an
earlier age; however, the lack of association between prostatitis and evidence of HSV-2 infection does not support
such a surveillance bias. As data regarding military PSA
screening rates were not available, we cannot comment
further on the potential screening bias among military personnel. Overall, present and prior findings suggest that additional research on how such infections may be related to
prostate cancer is needed.
Our study has several strengths including the choice
of a population with high rates of both prostate cancer
and STIs, including C. trachomatis, HSV-2, and HPV infections (8, 10, 11). Such high rates make both STIs and
prostate cancer important health issues for military personnel. As PSA screening is a covered health benefit in
the military, it seems more likely that prostate cancer
will be detected among military personnel than in men
in the general population. Although prostate cancer
rates in military personnel may be higher than in the
overall U.S. population due to better access to care
and more frequent PSA screening (introduced in 19871988; ref. 38), this study represents a large, fairly homogeneous cohort. Accurate exposure measurement is an
important issue when looking at STIs. However, many
studies of prostate cancer and STIs rely on self-report
and lack the specificity of biomarker laboratory data.
The major strength of this study is the availability for
examination of sera that were drawn several years before the diagnosis.
Although our study has several strengths, it also has
limitations. Unfortunately, PSA screening and cancer
stage data were not available in this electronic database.
The additional matching criteria on marital status and
race assigned by Department of Defense Serum Repository staff, which were not in the study protocol, may have
overmatched cases and controls on variables potentially
related to STIs as suggested in Table 1. This potential
overmatching likely made the control group more like
the cases and would tend to bias ORs toward 1.0. This
was supported by the larger ORs seen in single men
(for HSV-2) and Black non-Hispanic men (for HSV-2
and HPV; data not shown). We should note that a positive
or negative result for antibodies for a given serum sample
only reflects antibody levels at one point in time. C. trachomatis infection can be treated and cleared or may exist in
men with few or no symptoms. HPV infections may also
exist with few or no symptoms and may be cleared by the
body; thus, finding similar numbers of negative/positive
and positive/negative tests for HPV and Chlamydia was
not surprising. However, HSV-2 infection is often a chronic condition that is not cleared. Although all laboratory
tests have potential for error, indeterminate or borderline
antibody counts, particularly for HSV-2, could reflect no
recent infection before the blood draw for that serum
sample. Additionally, we do not know how long after
an infection or flare-up antibodies remain elevated. We
do not know if men in the military with STIs (other than
HIV) are followed and screened more than other men; if

so, this could account for the association seen here with
HSV-2 and prostate cancer but would not be consistent
with the lack of association between prostate cancer and
HPV or C. trachomatis infection.

Conclusion
We examined antibodies for HSV-2, several HPV types,
and C. trachomatis at an average of 94 and 10 months before prostate cancer diagnosis. Our findings suggest little
or no association with evidence of infections just before
the reference date. However, we did find an association
between prostate cancer and HSV-2 infection, which tends
to be a chronic infection, in sera collected an average of 7
years before diagnosis. If this association is real, it would
suggest that men diagnosed with HSV-2 should be encouraged to seek regular prostate cancer screening.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments
The costs of publication of this article were defrayed in part by
the payment of page charges. This article must therefore be
hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.

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